Learning disabilities are the most common behavioral deficit observed in children with Fetal Alcohol Spectrum Disorder. The development of effective pharmacotherapeutic interventions for these disabilities requires a clearer understanding of the neurobiologic bases of fetal ethanol-induced learning deficits and subsequently, the identification of therapeutic agents whose mechanisms of action would be predicted to have clinical utility. We have observed that the histamine H3 receptor antagonist ABT-239 ameliorates fetal ethanol-induced deficits in dentate gyrus long-term potentiation (LTP) and learning. We have also observed increased H3 receptor-effector coupling in dentate gyrus of fetal ethanol offspring. Given that presynaptic H3 receptors inhibit glutamate release;our results suggest that fetal ethanol exposure increases H3 receptor-mediated inhibition of glutamate release, and that ABT-239 reduces this heightened inhibitory influence. We hypothesize that: Fetal ethanol exposure elevates presynaptic histamine H3 receptor function in dentate gyrus. This heightened inhibitory influence reduces glutamate release at the perforant path - dentate granule cell synapse which, in turn, contributes to deficits in LTP and learned behaviors sensitive to functional damage in the dentate gyrus. To test this hypothesis, our specific aims will examine: 1: The binding of [3H]-A349821, a selective H3 receptor antagonist, in dentate gyrus to quantitate H3 receptor density in control and fetal alcohol offspring (Aim 1A). We will also use the selective H3 receptor agonist methimepip to conduct methimepip-displacement of [3H]-A349821 binding studies to determine the proportion of high- and low-affinity agonist binding sites of the H3 receptor (Aim 1B) and examine H3 receptor-effector coupling by measuring methimepip-stimulated [35S]-GTPgS binding (Aim 1C). 2: The effects of methimepip and ABT-239 on glutamate and GABA release by measuring paired-pulse plasticity and miniature postsynaptic currents along with the effects of these agents on LTP at perforant path dentate granule cell synapses in control and fetal ethanol-exposed offspring. 3: The effects of methimepip and ABT-239 on paired-pulse plasticity and LTP at the perforant path - granule cell synapse in vivo in control and fetal ethanol-exposed offspring. 4: The effects of methimepip on one-trial contextual fear conditioning (Aim 4A) and spatial navigation (Aim 4B) and the effects of methimepip and ABT-239 on a spatial pattern-separation variant of the radial arm maze (Aim 4C) in control and fetal ethanol-exposed offspring. We anticipate that these studies will provide important new insights on the impact of fetal ethanol exposure on histaminergic modulation of glutamatergic neurotransmission and synaptic plasticity in the dentate gyrus. In addition, the results could provide a preclinical pharmacologic rationale for considering drugs that act as H3 receptor antagonists as putative therapeutic agents for the treatment of learning deficits in humans with FASD. PUBLIC HEALTH RELEVANCE: Despite public awareness campaigns warning of the dangers of drinking during pregnancy, it is estimated that between 2% and 5% of children born in the United States each year have fetal alcohol-associated functional brain damage that will lead to learning deficits over time. Currently, there are no evidence-based clinically useful pharmacotherapeutic interventions for these deficits. The long-term objective of our research program is understand the neurobiologic bases of fetal ethanol-induced learning deficits and subsequently, to identify therapeutic agents whose mechanisms of action would be predicted to have clinical utility in treating fetal alcohol-associated learning disabilities.